Autor(es): Singh Kh Dhanachandra, Kirubakaran Palani, Nagarajan Shanthi, Sakkiah Sugunadevi, Muthusamy Karthikeyan, Velmurgan Devadasan, Jeyakanthan Jeyaraman

Resumo: To date, no suitable vaccine or specific antiviral drug is available to treat Chikungunya viral (CHIKV) fever. Hence, it is essential to identify drug c-idates that could potentially impede CHIKV infection. Here, we present the development of a homology model of nsP2 protein based on the crystal structure of the nsP2 protein of Venezuelan equine encephalitis virus (VEEV). The protein modeled was optimized using molecular dynamics simulation; the junction peptides of a nonstructural protein complex were then docked in order to investigate the possible protein-protein interactions between nsP2 - the proteins cleaved by nsP2. The modeling studies conducted shed light on the binding modes, - the critical interactions with the peptides provide insight into the chemical features needed to inhibit the CHIK virus infection. Energy-optimized pharmacophore mapping was performed using the junction peptides. Based on the results, we propose the pharmacophore features that must be present in an inhibitor of nsP2 protease. The resulting pharmacophore model contained an aromatic ring, a hydrophobic - three hydrogen-bond donor sites. Using these pharmacophore features, we screened a large public library of compounds (Asinex, Maybridge, TOSLab, Binding Database) to find a potential lig- that could inhibit the nsP2 protein. The compounds that yielded a fitness score of more than 1.0 were further subjected to Glide HTVS - Glide XP. Here, we report the best four compounds based on their docking scores; these compounds have IDs of 27943, 21362, ASN 01107557 - ASN 01541696. We propose that these compounds could bind to the active site of nsP2 protease - inhibit this enzyme. Furthermore, the backbone structural scaffolds of these four lead compounds could serve as building blocks when designing drug-like molecules for the treatment of Chikungunya viral fever.

Palavras-Chave: Chikungunya virus; Homology modeling; Desmond; Nonstructural proteins (nsP); Molecular dynamics simulation (MDS)

Imprenta: Journal of Molecular Modeling, v. 18, n. 1, p. 39-51, 2012

Identificador do objeto digital: 10.1007/s00894-011-1018-3

Descritores: Chikungunya virus - Biosynthesis ; Chikungunya virus - Molecular structure ; Chikungunya virus - Proteins ; Chikungunya virus - Viral infections ; Chikungunya Virus - Virus ; Chikungunya virus - Vaccine ; Chikungunya virus - Chikungunya fever

Data de publicação: 2012